Mini-ISES identifies promising carbafructopyranose-based salens for asymmetric catalysis: Tuning ligand shape via the anomeric effect

Abstract

This study introduces new methods of screening for and tuning chiral space and in so doing identifies a promising set of chiral ligands for asymmetric synthesis. The carbafructopyranosyl-1,2-diamine(s) and salens constructed therefrom are particularly compelling. It is shown that by removing the native anomeric effect in this ligand family, one can tune chiral ligand shape and improve chiral bias. This concept is demonstrated by a combination of (i) x-ray crystallographic structure determination, (ii) assessment of catalytic performance, and (iii) consideration of the anomeric effect and its underlying dipolar basis. The title ligands were identified by a new mini version of the in situ enzymatic screening (ISES) procedure through which catalyst-ligand combinations are screened in parallel, and information on relative rate and enantioselectivity is obtained in real time, without the need to quench reactions or draw aliquots. Mini-ISES brings the technique into the nanomole regime (200 to 350 nmol catalyst/20 μml organic volume) commensurate with emerging trends in reaction development/process chemistry. The best-performing β-d-carbafructopyranosyl-1,2-diamine-derived salen ligand discovered here outperforms the best known organometallic and enzymatic catalysts for the hydrolytic kinetic resolution of 3-phenylpropylene oxide, one of several substrates examined for which the ligand is "matched." This ligand scaffold defines a new swath of chiral space, and anomeric effect tunability defines a new concept in shaping that chiral space. Both this ligand set and the anomeric shape-tuning concept are expected to find broad application, given the value of chiral 1,2-diamines and salens constructed from these in asymmetric catalysis.

Fig. 1. “Privileged” chiral scaffolds.

(A) C₂-symmetric scaffolds for asymmetric catalysis. Cinchona alkaloids (teal); trans-1,2-diaminocyclohexane systems (blue); TADDOLates (orange); Phanephos-planar chirality, helically chiral bipyridyl-type ligand (wine); BINAP systems (green). (B) Non–C₂-symmetric scaffolds. Cinchona alkaloids (teal); trans-1,2-diaminocyclohexane-based Strecker catalyst (blue); proline-based systems-oxazaborolidine (red); Phanephos-planar chirality, helically chiral bipyridyl ligand (wine); planar chiral ferrocenyl phosphine systems (purple); CH-activated Ir-phosphoramidite catalyst (green). Arrows indicate the conversion of C₂-symmetric systems into non–C₂-symmetric systems.

Fig. 2. Depiction of the mini-ISES format for information-rich catalyst screening (ee, relative rate, and substrate scope).

(A) Quartz micromulticell in the background; reporting wells for catalyst derived from salen 16a in the foreground featuring both (S)- and (R)-selective dehydrogenase reporting enzymes for both propylene oxide (KRED 23 and TBADH, respectively) and hexane oxide (KRED 107 and KRED 119, respectively). The protein structure shown is the actual structure of TBADH (PDB 1YKF). (B) Actual ISES data for the HKR of the respective epoxides mediated by the Co(III)-salen catalyst derived from 16a in the lower organic layer (20 μl); spectral data reflect the conversion of NAD(P)⁺ to NAD(P)H upon diol oxidation by the respective reporting enzyme, with the concomitant increase in Abs_{340 nm} versus t (min).

Fig. 3. d-Fructopyranosyl-1,2-diamine synthesis.

Fig. 4. Synthesis of α- and β-d-carbafructopyranosyl-1,2-diamines from quinic acid.

Fig. 5. Three-dimensional bar graph for data from miniaturized ISES-for the Co-salen array.

(A) ISES data displayed in 3D format. (B) Comparison data from flask reactions (see the Supplementary Materials for details). (C) Sixteen-well quartz micromulticell used for mini-ISES. Note: Positive deflection = S-selective; blue, pink = HKR of hexane oxide; green, aqua = HKR of propylene oxide.

Fig. 6. X-ray crystal structures of Co-salen complexes reveal a correlation between anomeric effect and ligand shape in this ligand family.

(A) Schematic drawing of the proposed distortion of a ⁵C₂-like conformation into a ^3,6B-like conformation to minimize dipole-dipole repulsion in Co(II)-6c, as a manifestation of the anomeric effect. (B to D) X-ray crystal structures of (B) Co(II)-6c, (C) Co(II)-17c, and (D) Co(II)-6a.

Fig. 7. Chin structure versus transition-state model for the HKR of hexene oxide with catalyst Co(III)-17c.

(A) Chin’s Co(III)-salen-aziridine complex (second aziridine ligand omitted for clarity). (B) TS model for the HKR of hexane oxide with catalyst Co(III)-17c. Note: The catalyst structure was built from the x-ray coordinates of the Co(II)-17c structure (Fig. 6C) using the Chin structure as a guide in Spartan. The preferred substrate enantiomer, (S)-hexene oxide, was docked (Accelrys) at a Co–O coordination bond length of 1.99 Å, similar to the Co–N distance in the Chin structure. The O–Co–O–C dihedral angle θ in the TS model is at 24°, within the preferred range described by Jacobsen and co-workers.

Fig. 8. Streamlined access into the key intermediate toward the β-carbafructopyranosyl-1,2-diamines from d-mannose.

Fig. 9. Overview of the application of mini-ISES to the screening and identification of new chiral scaffolds for asymmetric catalysis.

A focused salen array is screening in parallel by UV/vis spectrophotometry using a micromulticell (20-μl organic layer) so as to bring catalyst loading down to the nanomolar level. Reporting enzyme output can then be processed to give an in situ readout on sense and magnitude of enantioselectivity. Out of this study, the cobalt-17c salen complex emerged as a particularly promising catalyst, indeed the best catalyst reported to date for the HKR of 3-phenyl propylene oxide.